Evaluation of individual subjects in the analog classroom setting: I. Examples of graphical and statistical procedures for within-subject ranking of responses to different delivery patterns of methylphenidate.

In this article, we describe graphical and statistical methods developed to evaluate the response patterns of individual children with attention deficit hyperactivity disorder (ADHD) to different conditions of treatment with stimulant medication. We used data from an investigation of drug delivery patterns to demonstrate these methods. Thirty-one children with ADHD participated in a double-blind crossover study of four conditions (three patterns of delivery of methylphenidate and a placebo control). In each condition, the children were evaluated across an 11-hour (7:00 a.m. to 6:00 p.m.) laboratory school day, and ratings of classroom behavior were obtained at regular intervals across the day. Graphical procedures were developed to display, for each individual, time courses of multiple measures of behavior taken across each double-blind test day. Expert clinicians judged these graphs and used this information to rank-order the test days from best to worst. A within-subject variant of Kendall's W was used to evaluate, for each subject, whether the rankings of these multidimensional graphs were reliable (concordant) across judges. A generalized kappa statistic was used to evaluate, for each condition, the reliability of the judges' rankings across subjects. Friedman's analysis of variance of ranks was used to evaluate, for the study, whether the conditions differed in terms of the average (consensus) rank assigned by the judges.

A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia.

Sertindole is a novel antipsychotic agent with high selectivity for the mesolimbic dopaminergic pathway and nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine NE alpha 1 receptors. This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n = 205). Sertindole doses began at 4 mg/day and were increased to 8, 12, or 20 mg/day, depending on randomization. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Extrapyramidal symptoms (EPS) were assessed by movement rating scales, EPS-related adverse events, and use of anti-EPS medications. A dose-related improvement was observed for PANSS, BPRS, and CGI, with statistically significant mean differences (P < 0.05) between placebo and 20-mg/day sertindole (decreases from baseline of -5.8 versus -16.9 for PANSS, -4.8 versus -10.4 for BPRS, respectively). The differences in CGI final improvement score between placebo and 20-mg/day sertindole were 3.8 versus 2.9, respectively. EPS-related events were comparable in the placebo and sertindole groups. In conclusion, sertindole 20 mg/day was effective, well tolerated, and not associated with significant motor system abnormalities.

Identification of middle ear effusion by aural acoustic admittance and otoscopy.

The ability of aural acoustic immittance measures and validated pneumatic otoscopy to identify middle ear effusion (MEE) was determined for a group of children with chronic or recurrent otitis media. The measures were made immediately prior to surgery for placement of tympanostomy tubes, with the validating diagnosis of MEE made by the surgeons. Aural acoustic admittance measures were made by a certified and licensed clinical audiologist using an instrument that meets current standards and otoscopic examinations were made by a nurse practitioner validated for use of otoscopy in the identification of MEE. Logistic regression analyses were done to determine the ability of admittance variables, otoscopy, and their combination to discriminate between ears with and ears without MEE. Of the individual admittance variables, tympanometric width had the best performance. Otoscopy alone had good sensitivity but only fair specificity. Combining acoustic admittance data with the otoscopist's findings did not improve sensitivity greatly, but improved the specificity relative to that of the otoscopist. The criterion tympanometric width > 150 daPa or Ytm < 0.2, a criterion commonly used based on interim norms published in an appendix of ASHA guidelines for screening, had good sensitivity but very poor specificity in the group of children scheduled for surgery. Also, a comparison was made for tympanometric width measures from the children undergoing surgery with those from a group of children more representative of the general population. Three distributions were found; one for ears with MEE, one for ears with no MEE of children scheduled for otologic surgery and one for ears with no MEE from the group of children from the general population. The data illustrate the importance of the population characteristics on the test measure used and have implications for choosing test criteria. In addition, group estimates of performance of acoustic admittance variables were approximately the same when otoscopy was used as the gold standard for identification of MEE as when findings at surgery were used. However, when comparing the two diagnostic methods on a case-by-case basis, it was determined that the otoscopist's diagnosis disagreed with the diagnosis of the surgeons in over 21% of the ears.

A comparative evaluation of cefaclor and amoxicillin in the treatment of acute otitis media.

In an earlier study of 214 children with acute otitis media (AOM) randomly assigned to a 14-day course of either cefaclor or amoxicillin, 55.7% of cefaclor-treated subjects were effusion-free compared with 41.2% of amoxicillin-treated subjects at the end of treatment. The present study was conducted to determine whether, in a 1-year period, subjects treated with cefaclor for each episode would have middle ear effusion for significantly less time than those treated with amoxicillin for each episode. One hundred fifty-seven subjects with AOM were enrolled. No statistically significant differences were found between the cefaclor-treated and amoxicillin-treated groups in number of subjects effusion-free immediately after first treatment (47.9% vs. 42.3%, respectively), average percent of time with effusion (22.2% vs. 23.4%, respectively), or in rate of new episodes of AOM (3.05 vs. 3.26, respectively). We conclude that there is no clinically significant advantage to the use of cefaclor rather than amoxicillin as the routine first line drug in the treatment of AOM.

Towards the validation of aural acoustic immittance measures for diagnosis of middle ear effusion in children.

Acoustic admittance testing was done on the ears of two groups of children. The first group was comprised of children undergoing myringotomy and tube surgery for treatment of chronic or recurrent otitis media, and the second group was comprised of hospital outpatients who were unscreened with respect to a history of middle ear disease and who were more representative of children in the general population. The admittance measures were then analyzed with respect to middle ear status (effusion versus no effusion) as determined by the surgeon (surgery group) and by validated otoscopy (outpatient group). Based on the data from the surgery group, the best admittance criteria for the identification of middle ear effusion were determined and then tested with respect to the data from subjects in the outpatient group. Sensitivity and specificity of several different criteria were similar. The role of prevalence of disease and the value of admittance measures such as gradient and acoustic reflex are discussed in the context of diagnostic testing in clinical or research protocols as well as in the context of immittance screening programs.

Rhinovirus 39 infection in allergic and nonallergic subjects.

To determine if individuals with allergic rhinitis are hyperresponsive to upper respiratory tract viral infections, 20 allergic and 18 nonallergic, susceptible, adult volunteers were challenged and infected with rhinovirus type 39 before the pollen seasons. Before challenge and on each of 6 days of cloister, all volunteers were interviewed for symptoms and completed a test battery consisting of evaluations of secretion production by weighed tissues, nasal patency by active posterior rhinomanometry, nasal clearance by the dyed saccharin technique, pulmonary function by spirometry, eustachian tube function by sonotubometry, and middle ear status by tympanometry. The symptomatology and pathophysiology resulting from the rhinovirus infection were consistent with those reported in previous studies with this challenge system. Between-group comparisons revealed no differences in symptom presentation, nasal secretion production, or overall pathophysiologic response. However, for decreased mucociliary clearance rate, increased nasal congestion, eustachian tube dysfunction, and symptoms of sneezing, the allergic group demonstrated an earlier onset compared with that of the nonallergic group. The biologic significance of the differences in onset of dysfunction is tempered by the observation that the temporal pattern of responses in the allergic group was similar with that of nonallergic subjects in previous studies. The results of the present study do not support the hypothesis of a physiologic hyperresponsiveness to rhinovirus type 39 infection in allergic subjects during nonallergy seasons.

Experimental otitis media evaluated by magnetic resonance imaging: an in vivo model.

The use of magnetic resonance imaging in otitis media research is being explored in our laboratory. In this study, we present a new method for studying changes in the middle ear cleft due to an episode of induced otitis media in the chinchilla model. It uses gadolinium-diethylenetriamine pentaacetic acid, a magnetic resonance imaging contrast agent, to examine the uptake and washout characteristics of middle ear mucosa during an inflammatory episode. Parameters such as the time to maximum intensity of the mucosa and the washout rate of the contrast agent from the mucosa were significantly correlated to the duration of the infection.

Efficacy of a new macrolide (azithromycin). For acute otitis media in the chinchilla model.

The efficacy of an investigational macrolide, azithromycin, in the treatment of acute otitis media consequent to an infection by a strain of beta-lactamase-producing Haemophilus influenzae, was evaluated using the chinchilla animal model. The results indicate that the azithromycin high-dosage (30 mg/kg/d) group has a significantly higher rate for effusion sterilization and resolution as compared with the other treatment groups. Unique pharmacokinetic properties of this investigational antimicrobial were demonstrated. Clinical trials using azithromycin for the treatment of upper respiratory tract infections, including otitis media, are warranted.